Cyclosporine A is well known for its immunosuppressive activity and a range of therapeutic uses, including antifungal, anti-parasitic, and anti-inflammatory as well as anti-HIV activity. Cyclosporine A and certain derivatives have been reported to inhibit the replication of hepatitis B virus DNA and HBsAg production in-vitro, see Xie et al, Acta Pharmacologica Sinica, 2007, Vol. 28, pp 975-984; Gallay et al., Gastroenterology 2015, Vol. 148(2), pp 403-414. This activity has been proposed to be dependent on the ability of said cyclosporine derivatives to bind to, and to inhibit, cyclophilins, see Gallay et al.
Hepatitis B, and D, viruses infect hepatocytes via interaction with the membrane transporter, sodium taurocholate co-transporting polypeptide (NTCP), see Yan et al., eLife 2012, 00049. Cyclosporine A and certain derivatives have been reported to inhibit the interaction of HBV, and HDV, with NTCP to block infection of hepatocytes in-vitro, see Urban et al., Journal of Hepatology 2014, Vol. 60, pp 723-731; Watashi et al., Hepatology 2014, Vol. 59, pp 1726-1737. This activity of cyclosporine A, and certain derivatives, described as ‘entry-inhibition’, is reported to be independent of the well described ability of cyclosporine derivatives to inhibit cyclophilins see Watashi et al., Hepatology 2014, Vol. 59, pp 1726-1737.
Cyclosporine A (cyclosporine) derivatives modified in the 1-position (Bmt) to introduce a tetrahydrofuran ring are known in the literature. For example, 6-[(2S)—N-methyl-2-[tetrahydro-5-(2-hydroxyethyl)-3-methyl-2-furanyl]glycine]-cyclosporin Ahas been described as a metabolite produced in certain animals, and man, following administration of cyclosporine A, see Maurer et al., Drug Metab. Dispos., 1984, 12, 120. The biological activity of this compound is described by Freed et al., Transplantation Proceed. 1991, vol. 23, pp 980-981. 6-[(2S)—N-methyl-2-[tetrahydro-5-(1-hydroxyethyl)-3-methyl-2-furanyl]glycine]-cyclosporin A is described by Liu et al., Clinical Biochemistry 1998, 31, 173-180 and was evaluated for immunosuppressive activity by Durette et al., Transplantation Proceed. 1988, vol. 2, pp 51-57. 6-[(2S)—N-methyl-2-[tetrahydro-5-(1-iodoethyl)-3-methyl-2-furanyl]glycine]-cyclosporin A is described as a reagent for cyclophilin binding assays and structural studies by Petcher et al., Helv. Chim. Acta. 1976, 59, 1480-8 and Mahony et al., Clinical Chemistry (Washington, D.C., USA) 1985, 31, 459-462. 6-[(2S)—N-methyl-2-[tetrahydro-5-(1-hydroxy-2-propenyl)-3-methyl-2-furanyl]glycine]-cyclosporin A is produced by microbial transformation as described by Freitag et al. in WO 2006066416. No antiviral activity is described for these compounds.